Summary Cardiac hypertrophy occurs in response to a variety of physiological and pathophysiological conditions. However, sustained cardiac hypertrophy plays an important role for the development of maladaptive cardiac remodeling leading to heart failure or sudden death. Although multiple signaling pathways have been shown to be implicated in the development of hypertrophy, it is poorly understood regarding the anti-hypertrophic pathways in the heart. FOXO3a is a transcriptional factor. Most recent studies show that it can negatively regulate cardiac hypertrophy. Cardiac hypertrophy can be mediated by the signaling molecules including reactive oxygen species (ROS). The cellular equilibrium of ROS is regulated by the antioxidant enzymes such as catalase. Our preliminary studies showed that FOXO3a is able to upregulate the expression of catalase in cardiomyocytes. Furthermore, knockdown of FOXO3a led to an increased level of ROS and cardiomyocyte hypertrophy. Administration of the antioxidant could attenuate hypertrophy upon FOXO3a knockdown. These observations lead us to hypothesize that "the regulation of FOXO3a on catalase constitutes an anti-hypertrophic pathway in the heart''. We will test this through studies under the following specific aims. Aim-1 will determine whether FOXO3a regulates hypertrophy by targeting catalase in the cellular model. Aim-2 will elucidate whether FOXO3a-catalase pathway is activated in the animal model. Aim-3 will characterize whether FOXO3a-catalase pathway is regulated by miRNAs. This proposed study will not only help us understand the role of FOXO3a-catalase in regulating cardiac hypertrophy, but could lead to further studies to explore the beneficial effect of this pathway as a biological target for the interventional treatment of maladaptive hypertrophy as well as heart failure. PUBLIC HEALTH RELEVANCE: Sustained cardiac hypertrophy has been proved to play an important role for the development of maladaptive cardiac remodeling leading to heart failure or sudden death. This project is to characterize whether the transcriptional regulation of FOXO3a on catalase constitutes an anti-hypertrophic pathway in the heart. The successful completion of project will provide important information for exploring the beneficial effects of this pathway in controlling hypertrophy as well as heart failure.